Methods and compositions for articular resurfacing

ABSTRACT

Disclosed herein are methods and compositions for producing articular repair materials and for repairing an articular surface. In particular, methods for providing articular replacement material, the method comprising the step of producing articular replacement material of selected size, curvature and/or thickness are provided. Also provided are articular surface repair systems designed to replace a selected area cartilage, for example, a system comprising at least one solid, non-pliable component and an external surface having near anatomic alignment to the surrounding structures.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.10/160,667 entitled “METHODS AND COMPOSITIONS FOR ARTICULARRESURFACING,” filed May 28, 2002, which in turn claims the benefit ofU.S. Ser. No. 60/293,488 entitled “METHODS TO IMPROVE CARTILAGE REPAIRSYSTEMS”, filed May 25, 2001, U.S. Ser. No. 60/363,527 entitled “NOVELDEVICES FOR CARTILAGE REPAIR, filed Mar. 12, 2002, U.S. Ser. No.60/380,695 entitled “METHODS AND COMPOSITIONS FOR CARTILAGE REPAIR,”filed May 14, 2002 and U.S. Ser. No. 60/380,692 entitled “METHODS FORJOINT REPAIR,” filed May 14, 2002, all of which applications are herebyincorporated by reference in their entireties.

TECHNICAL FIELD

The present invention relates to orthopedic methods, systems andprosthetic devices and more particularly relates to methods, systems anddevices for articular resurfacing.

BACKGROUND

There are various types of cartilage, e.g., hyaline cartilage andfibrocartilage. Hyaline cartilage is found at the articular surfaces ofbones, e.g., in the joints, and is responsible for providing the smoothgliding motion characteristic of moveable joints. Articular cartilage isfirmly attached to the underlying bones and measures typically less than5 mm in thickness in human joints, with considerable variation dependingon joint and site within the joint. In addition, articular cartilage isaneural, avascular, and alymphatic. In adult humans, this cartilagederives its nutrition by a double diffusion system through the synovialmembrane and through the dense matrix of the cartilage to reach thechondrocyte, the cells that are found in the connective tissue ofcartilage.

Adult cartilage has a limited ability of repair; thus, damage tocartilage produced by disease, such as rheumatoid and/or osteoarthritis,or trauma can lead to serious physical deformity and debilitation.Furthermore, as human articular cartilage ages, its tensile propertieschange. The superficial zone of the knee articular cartilage exhibits anincrease in tensile strength up to the third decade of life, after whichit decreases markedly with age as detectable damage to type II collagenoccurs at the articular surface. The deep zone cartilage also exhibits aprogressive decrease in tensile strength with increasing age, althoughcollagen content does not appear to decrease. These observationsindicate that there are changes in mechanical and, hence, structuralorganization of cartilage with aging that, if sufficiently developed,can predispose cartilage to traumatic damage.

Usually, severe damage or loss of cartilage is treated by replacement ofthe joint with a prosthetic material, for example, silicone, e.g. forcosmetic repairs, or metal alloys. See, e.g., U.S. Pat. No. 6,383,228,issued May 7, 2002; U.S. Pat. No. 6,203,576, issued Mar. 20, 2001; U.S.Pat. No. 6,126,690, issued Oct. 3, 2000. Implantation of prostheticdevices is usually associated with loss of underlying tissue and bonewithout recovery of the full function allowed by the original cartilage.Serious long-term complications associated with the presence of apermanent foreign body can include infection, osteolysis and alsoloosening of the implant.

Further, joint arthroplasties are highly invasive and require surgicalresection of the entire or the majority of the articular surface of oneor more bones. With these procedures, the marrow space is reamed inorder to fit the stem of the prosthesis. The reaming results in a lossof the patient's bone stock.

Osteolysis will frequently lead to loosening of the prosthesis. Theprosthesis will subsequently have to be replaced. Since the patient'sbone stock is limited, the number of possible replacement surgeries isalso limited for joint arthroplasty. In short, over the course of 15 to20 years, and in some cases shorter time periods, the patients may runout of therapeutic options resulting in a very painful, non-functionaljoint.

The use of matrices, tissue scaffolds or other carriers implanted withcells (e.g., chrondrocytes, chondrocyte progenitors, stromal cells,mesenchymal stem cells, etc.) has also been described as a potentialtreatment for cartilage repair. See, also, International PublicationsWO; 99/51719; WO 01/91672 and WO 01/17463; U.S. Pat. No. 5,283,980 B1,issued Sep. 4, 2001; U.S. Pat. No. 5,842,477, issued Dec. 1, 1998; U.S.Pat. No. 5,769,899, issued Jun. 23, 1998; U.S. Pat. No. 4,609,551,issued Sep. 2, 1986; U.S. Pat. No. 5,041,138, issued Aug. 20, 199; U.S.Pat. No. 5,197,985, issued Mar. 30, 1993; U.S. Pat. No. 5,226,914,issued Jul. 13, 1993; U.S. Pat. No. 6,328,765, issued Dec. 11, 2001;U.S. Pat. No. 6,281,195, issued Aug. 28, 2001; and U.S. Pat. No.4,846,835, issued Jul. 11, 1989. However, clinical outcomes withbiologic replacement materials such as allograft and autograft systemsand tissue scaffolds have been uncertain since most of these materialscannot achieve a morphologic arrangement or structure similar to oridentical to that of normal, disease-free human tissue. Moreover, themechanical durability of these biologic replacement materials is notcertain.

Despite the large number of studies in the area of cartilage repair, theintegration of the cartilage replacement material with the surroundingcartilage of the patient has proven difficult. In particular,integration can be extremely difficult due to differences in thicknessand curvature between the surrounding cartilage and/or the underlyingsubchondral bone and the cartilage replacement material.

Thus, there remains a need for methods and compositions for jointrepair, including methods and compositions that facilitate theintegration between the cartilage replacement system and the surroundingcartilage.

SUMMARY

The present invention provides novel devices and methods for replacing aportion (e.g., diseased area and/or area slightly larger than thediseased area) of a joint (e.g., cartilage and/or bone) with anon-pliable, non-liquid (e.g., hard) implant material, where the implantachieves a near anatomic fit with the surrounding structures andtissues. In cases where the devices and/or methods include an elementassociated with the underlying articular bone, the invention alsoprovides that the bone-associated element achieves a near anatomicalignment with the subchondral bone. The invention also provides for thepreparation of an implantation site a single cut.

In one aspect, the invention includes a method for providing articularreplacement material, the method comprising the step of producingarticular replacement (e.g., cartilage replacement material) of selecteddimensions (e.g., size, thickness and/or curvature).

In another aspect, the invention includes a method of making cartilagerepair material, the method comprising the steps of (a) measuring thedimensions (e.g., thickness, curvature and/or size) of the intendedimplantation site or the dimensions of the area surrounding the intendedimplantation site; and (b) providing cartilage replacement material thatconforms to the measurements obtained in step (a). In certain aspects,step (b) comprises measuring the thickness of the cartilage surroundingthe intended implantation site and measuring the curvature of thecartilage surrounding the intended implantation site. In otherembodiments, step (a) comprises measuring the size of the intendedimplantation site and measuring the curvature of the cartilagesurrounding the intended implantation site. In other embodiments, step(a) comprises measuring the thickness of the cartilage surrounding theintended implantation site, measuring the size of the intendedimplantation site, and measuring the curvature of the cartilagesurrounding the intended implantation site.

In any of the methods described herein, or more components of thearticular replacement material (e.g., the cartilage replacementmaterial) is non-pliable, non-liquid, solid or hard. The dimensions ofthe replacement material may be selected following intraoperativemeasurements, for example measurements made using imaging techniquessuch as ultrasound, MRI, CT scan, x-ray imaging obtained with x-ray dyeand fluoroscopic imaging. A mechanical probe (with or without imagingcapabilities) may also be used to selected dimensions, for example anultrasound probe, a laser, an optical probe and a deformable material.

In any of the methods described herein, the replacement material may beselected (for example, from a pre-existing library of repair systems),grown from cells and/or hardened from various materials. Thus, thematerial can be produced pre- or postoperatively. Furthermore, in any ofthe methods described herein the repair material may also be shaped(e.g., manually, automatically or by machine), for example usingmechanical abrasion, laser ablation, radiofrequency ablation,cryoablation and/or enzymatic digestion.

In any of the methods described herein, the articular replacementmaterial may comprise synthetic materials (e.g., metals, polymers,alloys or combinations thereof) or biological materials such as stemcells, fetal cells or chondrocyte cells.

In another aspect, the invention includes a method of repairing acartilage in a subject, the method of comprising the step ofimplantating cartilage repair material prepared according to any of themethods described herein.

In yet another aspect, the invention provides a method of determiningthe curvature of an articular surface, the method comprising the step of(a) intraoperatively measuring the curvature of the articular surfaceusing a mechanical probe. The articular surface may comprise cartilageand/or subchondral bone. The mechanical probe (with or without imagingcapabilities) may include, for example an ultrasound probe, a laser, anoptical probe and/or a deformable material.

In a still further aspect, the invention provides a method of producingan articular replacement material comprising the step of providing anarticular replacement material that conforms to the measurementsobtained by any of the methods of described herein.

In a still further aspect, the invention includes a partial articularprosthesis comprising a first component comprising a cartilagereplacement material; and a second component comprising one or moremetals, wherein said second component has a curvature similar tosubchondral bone, wherein said prosthesis comprises less than about 80%of the articular surface. In certain embodiments, the first and/orsecond component comprises a non-pliable material (e.g., a metal, apolymer, a metal allow, a solid biological material). Other materialsthat may be included in the first and/or second components includepolymers, biological materials, metals, metal alloys or combinationsthereof. Furthermore, one or both components may be smooth or porous (orporous coated). In certain embodiments, the first component exhibitsbiomechanical properties (e.g., elasticity, resistance to axial loadingor shear forces) similar to articular cartilage. The first and/or secondcomponent can be bioresorbable and, in addition, the first or secondcomponents may be adapted to receive injections.

In another aspect, a partial articular prosthesis comprising an externalsurface located in the load bearing area of an articular surface,wherein the dimensions of said external surface achieve a near anatomicfit with the adjacent cartilage is provided. The prosthesis of mayfurther comprise one or more metals or metal alloys.

In yet another aspect, an articular repair system comprising (a)cartilage replacement material, wherein said cartilage replacementmaterial has a curvature similar to surrounding or adjacent cartilage;and (b) at least one non-biologic material, wherein said articularsurface repair system comprises a portion of the articular surface equalto or smaller than the weight-bearing surface is provided. In certainembodiments, the cartilage replacement material is non-pliable (e.g.,hard hydroxyapatite, etc.). In certain embodiments, the system exhibitsbiomechanical (e.g., elasticity, resistance to axial loading or shearforces) and/or biochemical properties similar to articular cartilage.The first and/or second component can be bioresorbable and, in addition,the first or second components may be adapted to receive injections.

In a still further aspect of the invention, an articular surface repairsystem comprising a first component comprising a cartilage replacementmaterial, wherein said first component has dimensions similar to that ofadjacent or surrounding cartilage; and a second component, wherein saidsecond component has a curvature similar to subchondral bone, whereinsaid articular surface repair system comprises less than about 80% ofthe articular surface (e.g., a single femoral condyle, tibia, etc.) isprovided. In certain embodiments, the first component is non-pliable(e.g., hard hydroxyapatite, etc.). In certain embodiments, the systemexhibits biomechanical (e.g., elasticity, resistance to axial loading orshear forces) and/or biochemical properties similar to articularcartilage. The first and/or second component can be bioresorbable and,in addition, the first or second components may be adapted to receiveinjections. In certain embodiments, the first component has a curvatureand thickness similar to that of adjacent or surrounding cartilage. Thethickness and/or curvature may vary across the implant material.

In a still further embodiment, a partial articular prosthesis comprising(a) a metal or metal alloy; and (b) an external surface located in theload bearing area of an articular surface, wherein the external surfacedesigned to achieve a near anatomic fit with the adjacent cartilage isprovided.

Any of the repair systems or prostheses described herein (e.g., theexternal surface) may comprise a polymeric material, for exampleattached to said metal or metal alloy. Further, any of the systems orprostheses described herein can be adapted to receive injections, forexample, through an opening in the external surface of said cartilagereplacement material (e.g., an opening in the external surfaceterminates in a plurality of openings on the bone surface). Bone cement,therapeutics, and/or other bioactive substances may be injected throughthe opening(s). In certain embodiments, bone cement is injected underpressure in order to achieve permeation of portions of the marrow spacewith bone cement.

These and other embodiments of the subject invention will readily occurto those of skill in the art in light of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a flowchart depicting various methods of the present inventionincluding, measuring the size of an area of diseased cartilage orcartilage loss, measuring the thickness of the adjacent cartilage, andmeasuring the curvature of the articular surface and/or subchondralbone. Based on this information, a best fitting implant can be selectedfrom a library of implants or a patient specific custom implant can begenerated. The implantation site is subsequently prepared and theimplantation is performed.

FIG. 2 is a reproduction of a three-dimensional thickness map of thearticular cartilage of the distal femur. Three-dimensional thicknessmaps can be generated, for example, from ultrasound, CT or MRI data.Dark holes within the substances of the cartilage indicate areas of fullthickness cartilage loss.

FIG. 3 shows an example of a Placido disc of concentrically arrangedcircles of light.

FIG. 4 shows an example of a projected Placido disc on a surface offixed curvature.

FIG. 5 shows an example of a 2D topographical map of an irregularlycurved surface.

FIG. 6 shows an example of a 3D topographical map of an irregularlycurved surface.

FIG. 7 shows a reflection resulting from a projection of concentriccircles of light (Placido Disk) on each femoral condyle, demonstratingthe effect of variation in surface contour on the reflected circles.

FIGS. 8A-H are schematics of various stages of knee resurfacing. FIG. 8Ashows an example of normal thickness cartilage in the anterior, centraland posterior portion of a femoral condyle 800 and a cartilage defect805 in the posterior portion of the femoral condyle. FIG. 8B shows animaging technique or a mechanical, optical, laser or ultrasound devicemeasuring the thickness and detecting a sudden change in thicknessindicating the margins of a cartilage defect 810. FIG. 8C shows aweight-bearing surface 815 mapped onto the articular cartilage.Cartilage defect 805 is located within the weight-bearing surface 815.FIG. 8D shows an intended implantation site (stippled line) 820 andcartilage defect 805. The implantation site 820 is slightly larger thanthe area of diseased cartilage 805. FIG. 8E depicts placement of asingle component articular surface repair system 825. The externalsurface of the articular surface repair system 826 has a curvaturesimilar to that of the surrounding cartilage 800 resulting in goodpostoperative alignment between the surrounding normal cartilage 800 andthe articular surface repair system 825. FIG. 8F shows an exemplarymulti-component articular surface repair system 830. The distal surfaceof the deep component 832 has a curvature similar to that of theadjacent subchondral bone 835. The external surface of the superficialcomponent 837 has a thickness and curvature similar to that of thesurrounding normal cartilage 800. FIG. 8G shows an exemplary singlecomponent articular surface repair system 840 with a peripheral margin845 substantially non-perpendicular to the surrounding or adjacentnormal cartilage 800. FIG. 8H shows an exemplary multi-componentarticular surface repair system 850 with a peripheral margin 845substantially non-perpendicular to the surrounding or adjacent normalcartilage 800.

FIG. 9, A through E, are schematics depicting exemplary knee imaging andresurfacing. FIG. 9A is a schematic depicting a magnified view of anarea of diseased cartilage 905 demonstrating decreased cartilagethickness when compared to the surrounding normal cartilage 900. Themargins 910 of the defect have been determined. FIG. 9B is a schematicdepicting measurement of cartilage thickness 915 adjacent to the defect905. FIG. 9C is a schematic depicting placement of a multi-componentmini-prosthesis 915 for articular resurfacing. The thickness 920 of thesuperficial component 923 closely approximates that of the adjacentnormal cartilage 900 and varies in different regions of the prosthesis.The curvature of the distal portion of the deep component 925 is similarto that of the adjacent subchondral bone 930. FIG. 9D is a schematicdepicting placement of a single component mini-prosthesis 940 utilizingfixturing stems 945. FIG. 9E depicts placement of a single componentmini-prosthesis 940 utilizing fixturing stems 945 and an opening 950 forinjection of bone cement 955. The mini-prosthesis has an opening at theexternal surface 950 for injecting bone cement 955 or other liquids. Thebone cement 955 can freely extravasate into the adjacent bone and marrowspace from several openings at the undersurface of the mini-prosthesis960 thereby anchoring the mini-prosthesis.

FIGS. 10A to C, are schematics depicting other exemplary kneeresurfacing devices and methods. FIG. 10A is a schematic depictingnormal thickness cartilage in the anterior and central and posteriorportion of a femoral condyle 1000 and a large area of diseased cartilage1005 in the posterior portion of the femoral condyle. FIG. 10B depictsplacement of a single component articular surface repair system 1010.The implantation site has been prepared with a single cut. The articularsurface repair system is not perpendicular to the adjacent normalcartilage 1000. FIG. 10C depicts a multi-component articular surfacerepair system 1020. The implantation site has been prepared with asingle cut. The deep component 1030 has a curvature similar to that ofthe adjacent subchondral bone 1035. The superficial component 1040 has acurvature similar to that of the adjacent cartilage 1000.

FIGS. 11A and B show exemplary single and multiple component devices.FIG. 11A shows an exemplary a single component articular surface repairsystem 1100 with varying curvature and radii. In this case, thearticular surface repair system is chosen to include convex and concaveportions. Such devices can be preferable in a lateral femoral condyle orsmall joints such as the elbow joint. FIG. 11B depicts a multi-componentarticular surface repair system with a deep component 1110 that mirrorsthe shape of the subchondral bone and a superficial component 1105closely matching the shape and curvature of the surrounding normalcartilage 1115. The deep component 1110 and the superficial component1105 demonstrate varying curvatures and radii with convex and concaveportions.

DETAILED DESCRIPTION OF THE INVENTION

The current invention provides for methods and devices for integrationof cartilage replacement or regenerating materials.

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular formulationsor process parameters as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments of the invention only, and is notintended to be limiting.

The practice of the present invention employs, unless otherwiseindicated, conventional methods of x-ray imaging and processing, x-raytomosynthesis, ultrasound including A-scan, B-scan and C-scan, computedtomography (CT scan), magnetic resonance imaging (MRI), opticalcoherence tomography, single photon emission tomography (SPECT) andpositron emission tomography (PET) within the skill of the art. Suchtechniques are explained fully in the literature. See, e.g., X-RayStructure Determination: A Practical Guide, 2nd Edition, editors Stoutand Jensen, 1989, John Wiley & Sons, publisher; Body CT: A PracticalApproach, editor Slone, 1999, McGraw-Hill publisher; X-ray Diagnosis: APhysician's Approach, editor Lam, 1998 Springer-Verlag, publisher; andDental Radiology: Understanding the X-Ray Image, editor LaetitiaBrocklebank 1997, Oxford University Press publisher.

All publications, patents and patent applications cited herein, whetherabove or below, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include pluralreferences unless the content clearly dictates otherwise. Thus, forexample, reference to “an implantation site” includes a one or more suchsites.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice for testing of the present invention, the preferredmaterials and methods are described herein.

The term “arthritis” refers to a group of conditions characterized byprogressive deterioration of joints. Thus, the term encompasses a groupof different diseases including, but not limited to, osteoarthritis(OA), rheumatoid arthritis, seronegative spondyloarthropathies andposttraumatic joint deformity.

The term “articular” refers to any joint. Thus, “articular cartilage”refers to cartilage in a joint such as a knee, ankle, hip, etc. The term“articular surface” refers to a surface of an articulating bone that iscovered by cartilage. For example, in a knee joint several differentarticular surfaces are present, e.g. in the patella, the medial femoralcondyle, the lateral femoral condyle, the medial tibial plateau and thelateral tibial plateau.

The term “weight-bearing surface” refers to the contact area between twoopposing articular surfaces during activities of normal daily living.

The term “cartilage” or “cartilage tissue” as used herein is generallyrecognized in the art, and refers to a specialized type of denseconnective tissue comprising cells embedded in an extracellular matrix(ECM) (see, for example, Cormack, 1987, Ham's Histology, 9th Ed., J. B.Lippincott Co., pp. 266-272). The biochemical composition of cartilagediffers according to type Several types of cartilage are recognized inthe art, including, for example, hyaline cartilage such as that foundwithin the joints, fibrous cartilage such as that found within themeniscus and costal regions, and elastic cartilage. Hyaline cartilage,for example, comprises chondrocytes surrounded by a dense ECM consistingof collagen, proteoglycans and water. Fibrocartilage can form in areasof hyaline cartilage, for example after an injury or, more typically,after certain types of surgery. The production of any type of cartilageis intended to fall within the scope of the invention.

Furthermore, although described primarily in relation to methods for usein humans, the invention may also be practiced so as repair cartilagetissue in any mammal in need thereof, including horses, dogs, cats,sheep, pigs, among others. The treatment of such animals is intended tofall within the scope of the invention.

The terms “articular repair system” and “articular surface repairsystem” include any system (including, for example, compositions,devices and techniques) to repair, to replace or to regenerate a portionof a joint or an entire joint. The term encompasses systems that repairarticular cartilage, articular bone or both bone and cartilage.Articular surface repair systems may also include a meniscal repairsystem (e.g., meniscal repair system can be composed of a biologic ornon-biologic material), for example a meniscal repair system havingbiomechanical and/or biochemical properties similar to that of healthymenisci. See, for example, U.S. Patent Publication No. US2002/00228841A1. The meniscal repair system can be surgically orarthroscopically attached to the joint capsule or one or more ligaments.Non-limiting examples of repair systems include autologous chondrocytetransplantation, osteochondral allografting, osteochondral autografting,tibial corticotomy, femoral and/or tibial osteotomy. Repair systems alsoinclude treatment with cartilage or bone tissue grown ex vivo, stemcells, cartilage material grown with use of stem cells, fetal cells orimmature or mature cartilage cells, an artificial non-human material, anagent that stimulates repair of diseased cartilage tissue, an agent thatstimulates growth of cells, an agent that protects diseased cartilagetissue and that protects adjacent normal cartilage tissue. Articularrepair systems include also treatment with a cartilage tissuetransplant, a cartilage tissue graft, a cartilage tissue implant, acartilage tissue scaffold, or any other cartilage tissue replacement orregenerating material. Articular repair systems include also surgicaltools that facilitate the surgical procedure required for articularrepair, for example tools that prepare the area of diseased cartilagetissue and/or subchondral bone for receiving, for example, a cartilagetissue replacement or regenerating material. The term “non-pliable”refers to material that cannot be significantly bent but may retainelasticity.

The terms “replacement material” or “regenerating material” include abroad range of natural and/or synthetic materials used in the methodsdescribed herein, for example, cartilage or bone tissue grown ex vivo,stem cells, cartilage material grown from stem cells, stem cells, fetalcell, immature or mature cartilage cells, an agent that stimulatesgrowth of cells, an artificial non-human material, a cartilage tissuetransplant, a cartilage tissue graft, a cartilage tissue implant, acartilage tissue scaffold, or a cartilage tissue regenerating material.The term includes biological materials isolated from various sources(e.g., cells) as well as modified (e.g., genetically modified) materialsand/or combinations of isolated and modified materials.

The term “imaging test” includes, but is not limited to, x-ray basedtechniques (such as conventional film based x-ray films, digital x-rayimages, single and dual x-ray absorptiometry, radiographicabsorptiometry); digital x-ray tomosynthesis, x-ray imaging includingdigital x-ray tomosynthesis with use of x-ray contrast agents, forexample after intra-articular injection, ultrasound including broadbandultrasound attenuation measurement and speed of sound measurements,A-scan, B-scan and C-scan; computed tomography; nuclear scintigraphy;SPECT; positron emission tomography, optical coherence tomography andMRI. One or more of these imaging tests may be used in the methodsdescribed herein, for example in order to obtain certain morphologicalinformation about one or several tissues such as bone including bonemineral density and curvature of the subchondral bone, cartilageincluding biochemical composition of cartilage, cartilage thickness,cartilage volume, cartilage curvature, size of an area of diseasedcartilage, severity of cartilage disease or cartilage loss, marrowincluding marrow composition, synovium including synovial inflammation,lean and fatty tissue, and thickness, dimensions and volume of soft andhard tissues. The imaging test can be performed with use of a contrastagent, such as Gd-DTPA in the case of MRI. The term “A-scan” refers toan ultrasonic technique where an ultrasonic source transmits anultrasonic wave into an object, such as patient's body, and theamplitude of the returning echoes (signals) are recorded as a functionof time. Only structures that lie along the direction of propagation areinterrogated. As echoes return from interfaces within the object ortissue, the transducer crystal produces a voltage that is proportionalto the echo intensity. The sequence of signal acquisition and processingof the A-scan data in a modem ultrasonic instrument usually occurs insix major steps:

(1) Detection of the echo (signal) occurs via mechanical deformation ofthe piezoelectric crystal and is converted to an electric signal havinga small voltage.

(2) Preamplification of the electronic signal from the crystal, into amore useful range of voltages is usually necessary to ensure appropriatesignal processing.

(3) Time Gain Compensation compensates for the attenuation of theultrasonic signal with time, which arises from travel distance. Timegain compensation may be user-adjustable and may be changed to meet theneeds of the specific application. Usually, the ideal time gaincompensation curve corrects the signal for the depth of the reflectiveboundary. Time gain compensation works by increasing the amplificationfactor of the signal as a function of time after the ultrasonic pulsehas been emitted. Thus, reflective boundaries having equal abilities toreflect ultrasonic waves will have equal ultrasonic signals, regardlessof the depth of the boundary.

(4) Compression of the time compensated signal can be accomplished usinglogarithmic amplification to reduce the large dynamic range (range ofsmallest to largest signals) of the echo amplitudes. Small signals aremade larger and large signals are made smaller. This step provides aconvenient scale for display of the amplitude variations on the limitedgray scale range of a monitor.

(5) Rectification, demodulation and envelope detection of the highfrequency electronic signal permits the sampling and digitization of theecho amplitude free of variations induced by the sinusoidal nature ofthe waveform.

(6) Rejection level adjustment sets the threshold of signal amplitudesthat are permitted to enter a data storage, processing or displaysystem. Rejection of lower signal amplitudes reduces noise levels fromscattered ultrasonic signals.

The term “B-scan” refers to an ultrasonic technique where the amplitudeof the detected returning echo is recorded as a function of thetransmission time, the relative location of the detector in the probeand the signal amplitude. This is often represented by the brightness ofa visual element, such as a pixel, in a two-dimensional image. Theposition of the pixel along the y-axis represents the depth, i.e. halfthe time for the echo to return to the transducer (for one half of thedistance traveled). The position along the x-axis represents thelocation of the returning echoes relative to the long axis of thetransducer, i.e. the location of the pixel either in a superoinferior ormediolateral direction or a combination of both. The display of multipleadjacent scan lines creates a composite two-dimensional image thatportrays the general contour of internal organs.

The term “C-scan” refers to an ultrasonic technique where additionalgating electronics are incorporated into a B-scan to eliminateinterference from underlying or overlying structures by scanning at aconstant-depth. An interface reflects part of the ultrasonic beamenergy. All interfaces along the scan line may contribute to themeasurement. The gating electronics of the C-mode rejects all returningechoes except those received during a specified time interval. Thus,only scan data obtained from a specific depth range are recorded.Induced signals outside the allowed period are not amplified and, thus,are not processed and displayed. C-mode-like methods are also describedherein for A-scan techniques and devices in order to reduce theprobe/skin interface reflection. The term “repair” is used in a broadsense to refer to one or more repairs to damaged joints (e.g., cartilageor bone) or to replacement of one or more components or regions of thejoint. Thus, the term encompasses both repair (e.g., one or moreportions of a cartilage and/or layers of cartilage or bone) andreplacement (e.g., of an entire cartilage).

General Overview

The present invention provides methods and compositions for repairingjoints, particularly for repairing articular cartilage and forfacilitating the integration of a wide variety of cartilage repairmaterials into a subject. Among other things, the techniques describedherein allow for the customization of cartilage repair material to suita particular subject, for example in terms of size, cartilage thicknessand/or curvature. When the shape (e.g., size, thickness and/orcurvature) of the articular cartilage surface is an exact or nearanatomic fit with the non-damaged cartilage or with the subjectsoriginal cartilage, the success of repair is enhanced. The repairmaterial may be shaped prior to implantation and such shaping can bebased, for example, on electronic images that provide informationregarding curvature or thickness of any “normal” cartilage surroundingthe defect and/or on curvature of the bone underlying the defect. Thus,the current invention provides, among other things, for minimallyinvasive methods for partial joint replacement. The methods will requireonly minimal or, in some instances, no loss in bone stock. Additionally,unlike with current techniques, the methods described herein will helpto restore the integrity of the articular surface by achieving an exactor near anatomic match between the implant and the surrounding oradjacent cartilage and/or subchondral bone.

Advantages of the present invention can include, but are not limited to,(i) customization of joint repair, thereby enhancing the efficacy andcomfort level for the patient following the repair procedure; (ii)eliminating the need for a surgeon to measure the defect to be repairedintraoperatively in some embodiments; (iii) eliminating the need for asurgeon to shape the material during the implantation procedure; (iv)providing methods of evaluating curvature of the repair material basedon bone or tissue images or based on intraoperative probing techniques;(v) providing methods of repairing joints with only minimal or, in someinstances, no loss in bone stock; and (vi) improving postoperative jointcongruity.

Thus, the methods described herein allow for the design and use of jointrepair material that more precisely fits the defect (e.g., site ofimplantation) and, accordingly, provides improved repair of the joint.

1.0. Assessment of Defects

The methods and compositions described herein may be used to treatdefects resulting from disease of the cartilage (e.g., osteoarthritis),bone damage, cartilage damage, trauma, and/or degeneration due tooveruse or age. The invention allows, among other things, a healthpractitioner to evaluate and treat such defects. The size, volume andshape of the area of interest may include only the region of cartilagethat has the defect, but preferably will also include contiguous partsof the cartilage surrounding the cartilage defect.

Size, curvature and/or thickness measurements can be obtained using anysuitable techniques, for example in one direction, two directions,and/or in three dimensions for example, using suitable mechanical means,laser devices, molds, materials applied to the articular surface thatharden and “memorize the surface contour,” and/or one or more imagingtechniques. Measurements may be obtained non-invasively and/orintraoperatively (e.g., using a probe or other surgical device).

1.1. Imaging Techniques

Non-limiting examples of imaging techniques suitable for measuringthickness and/or curvature (e.g., of cartilage and/or bone) or size ofareas of diseased cartilage or cartilage loss include the use of x-rays,magnetic resonance imaging (MRI), computed tomography scanning (CT, alsoknown as computerized axial tomography or CAT), optical coherencetomography, SPECT, PET, ultrasound imaging techniques, and opticalimaging techniques. (See, also, International Patent Publication WO02/22014; U.S. Pat. No. 6,373,250 and Vandeberg et al. (2002) Radiology222:430-436).

In certain embodiments, CT or MRI is used to assess tissue, bone,cartilage and any defects therein, for example cartilage lesions orareas of diseased cartilage, to obtain information on subchondral boneor cartilage degeneration and to provide morphologic or biochemical orbiomechanical information about the area of damage. Specifically,changes such as fissuring, partial or full thickness cartilage loss, andsignal changes within residual cartilage can be detected using one ormore of these methods. For discussions of the basic NMR principles andtechniques, see MRI Basic Principles and Applications, Second Edition,Mark A. Brown and Richard C. Semelka, Wiley-Liss, Inc. (1999). For adiscussion of MRI including conventional T1 and T2-weighted spin-echoimaging, gradient recalled echo (GRE) imaging, magnetization transfercontrast (MTC) imaging, fast spin-echo (FSE) imaging, contrast enhancedimaging, rapid acquisition relaxation enhancement, (RARE) imaging,gradient echo acquisition in the steady state, (GRASS), and drivenequilibrium Fourier transform (DEFT) imaging, to obtain information oncartilage, see WO 02/22014. Thus, in preferred embodiments, themeasurements are three-dimensional images obtained as described in WO02/22014. Three-dimensional internal images, or maps, of the cartilagealone or in combination with a movement pattern of the joint can beobtained. Three-dimensional internal images can include information onbiochemical composition of the articular cartilage. In addition, imagingtechniques can be compared over time, for example to provide up to dateinformation on the size and type of repair material needed.

Any of the imaging devices described herein may also be usedintra-operatively (see, also below), for example using a hand-heldultrasound and/or optical probe to image the articular surfaceintra-operatively.

1.2. Intra-Operative Measurements

Alternatively, or in addition to, non-invasive imaging techniques,measurements of the size of an area of diseased cartilage or an area ofcartilage loss, measurements of cartilage thickness and/or curvature ofcartilage or bone can be obtained intraoperatively during arthroscopy oropen arthrotomy. Intraoperative measurements may or may not involveactual contact with one or more areas of the articular surfaces.

Devices to obtain intraoperative measurements of cartilage, and togenerate a topographical map of the surface include but are not limitedto, Placido disks and laser interferometers, and/or deformablematerials. (See, for example, U.S. Pat. Nos. 6,382,028; 6,057,927;5,523,843; 5,847,804; and 5,684,562). For example, a Placido disk (aconcentric array that projects well-defined circles of light of varyingradii, generated either with laser or white light transported viaoptical fiber) can be attached to the end of an endoscopic device (or toany probe, for example a hand-held probe) so that the circles of lightare projected onto the cartilage surface. One or more imaging camerascan be used (e.g., attached to the device) to capture the reflection ofthe circles. Mathematical analysis is used to determine the surfacecurvature. The curvature can then be visualized on a monitor as acolor-coded, topographical map of the cartilage surface. Additionally, amathematical model of the topographical map can be used to determine theideal surface topography to replace any cartilage defects in the areaanalyzed. This computed, ideal surface can then also be visualized onthe monitor, and is used to select the curvature of the replacementmaterial or regenerating material.

Similarly a laser interferometer can also be attached to the end of anendoscopic device. In addition, a small sensor may be attached to thedevice in order to determine the cartilage surface curvature using phaseshift interferometry, producing a fringe pattern analysis phase map(wave front) visualization of the cartilage surface. The curvature canthen be visualized on a monitor as a color coded, topographical map ofthe cartilage surface. Additionally, a mathematical model of thetopographical map can be used to determine the ideal surface topographyto replace any cartilage defects in the area analyzed. This computed,ideal surface can then also visualized on the monitor, and can be usedto select the curvature of the replacement cartilage.

One skilled in the art will readily recognize other techniques foroptical measurements of the cartilage surface curvature.

Mechanical devices (e.g., probes) may also be used for intraoperativemeasurements, for example, deformable materials such as gels, molds, anyhardening materials (e.g., materials that remain deformable until theyare heated, cooled, or otherwise manipulated). See, e.g., WO 02/34310.For example, a deformable gel can be applied to a femoral condyle. Theside of the gel pointing towards the condyle will yield a negativeimpression of the surface contour of the condyle. Said negativeimpression can be used to determine the size of a defect, the depth of adefect and the curvature of the articular surface in and adjacent to adefect. This information can be used to select a therapy, e.g. anarticular surface repair system. In another example, a hardeningmaterial can be applied to an articular surface, e.g. a femoral condyleor a tibial plateau. Said hardening material will remain on thearticular surface until hardening has occurred. The hardening materialwill then be removed from the articular surface. The side of thehardening material pointing towards the articular surface will yield anegative impression of the articular surface. The negative impressioncan be used to determine the size of a defect, the depth of a defect andthe curvature of the articular surface in and adjacent to a defect. Thisinformation can be used to select a therapy, e.g. an articular surfacerepair system.

In certain embodiments, the deformable material comprises a plurality ofindividually moveable mechanical elements. When pressed against thesurface of interest, each element may be pushed in the opposingdirection and the extent to which it is pushed (deformed) willcorrespond to the curvature of the surface of interest. The device mayinclude a brake mechanism so that the elements are maintained in theposition that mirrors the surface of the cartilage and/or bone. Thedevice can then be removed from the patient and analyzed for curvature.Alternatively, each individual moveable element may include markersindicating the amount and/or degree they are deformed at a given spot. Acamera can be used to intra-operatively image the device and the imagecan be saved and analyzed for curvature information. Suitable markersinclude, but are not limited to, actual linear measurements (metric orimperial), different colors corresponding to different amounts ofdeformation and/or different shades or hues of the same color(s).

Other devices to measure cartilage and subchondral bone intraoperativelyinclude, for example, ultrasound probes. An ultrasound probe, preferablyhandheld, can be applied to the cartilage and the curvature of thecartilage and/or the subchondral bone can be measured. Moreover, thesize of a cartilage defect can be assessed and the thickness of thearticular cartilage can be determined. Such ultrasound measurements canbe obtained in A-mode, B-mode, or C-mode. If A-mode measurements areobtained, an operator will typically repeat the measurements withseveral different probe orientations, e.g. mediolateral andanteroposterior, in order to derive a three-dimensional assessment ofsize, curvature and thickness.

One skilled in the art will easily recognize that different probedesigns are possible using said optical, laser interferometry,mechanical and ultrasound probes. The probes are preferably handheld. Incertain embodiments, the probes or at least a portion of the probe,typically the portion that is in contact with the tissue, will besterile. Sterility can be achieved with use of sterile covers, forexample similar to those disclosed in WO9908598A1.

Analysis on the curvature of the articular cartilage or subchondral boneusing imaging tests and/or intraoperative measurements can be used todetermine the size of an area of diseased cartilage or cartilage loss.For example, the curvature can change abruptly in areas of cartilageloss. Such abrupt or sudden changes in curvature can be used to detectthe boundaries of diseased cartilage or cartilage defects.

1.3. Models

Using information on thickness and curvature of the cartilage, aphysical model of the surfaces of the articular cartilage and of theunderlying bone can be created. This physical model can berepresentative of a limited area within the joint or it can encompassthe entire joint. For example, in the knee joint, the physical model canencompass only the medial or lateral femoral condyle, both femoralcondyles and the notch region, the medial tibial plateau, the lateraltibial plateau, the entire tibial plateau, the medial patella, thelateral patella, the entire patella or the entire joint. The location ofa diseased area of cartilage can be determined, for example using a 3Dcoordinate system or a 3D Euclidian distance as described in WO02/22014.

In this way, the size of the defect to be repaired can be determined. Aswill be apparent, some, but not all, defects will include less than theentire cartilage. Thus, in one embodiment of the invention, thethickness of the normal or only mildly diseased cartilage surroundingone or more cartilage defects is measured. This thickness measurementcan be obtained at a single point or, preferably, at multiple points,for example 2 point, 4-6 points, 7-10 points, more than 10 points orover the length of the entire remaining cartilage. Furthermore, once thesize of the defect is determined, an appropriate therapy (e.g.,articular repair system) can be selected such that as much as possibleof the healthy, surrounding tissue is preserved.

In other embodiments, the curvature of the articular surface can bemeasured to design and/or shape the repair material. Further, both thethickness of the remaining cartilage and the curvature of the articularsurface can be measured to design and/or shape the repair material.Alternatively, the curvature of the subchondral bone can be measured andthe resultant measurement(s) can be used to either select or shape acartilage replacement material.

2.0. Repair Materials

A wide variety of materials find use in the practice of the presentinvention, including, but not limited to, plastics, metals, ceramics,biological materials (e.g., collagen or other extracellular matrixmaterials), hydroxyapatite, cells (e.g., stem cells, chondrocyte cellsor the like), or combinations thereof. Based on the information (e.g.,measurements) obtained regarding the defect and the articular surfaceand/or the subchondral bone, a repair material can be formed orselected. Further, using one or more of these techniques describedherein, a cartilage replacement or regenerating material having acurvature that will fit into a particular cartilage defect, will followthe contour and shape of the articular surface, and will match thethickness of the surrounding cartilage can be made. The repair materialmay include any combination of materials, and preferably includes atleast one non-pliable (hard) material.

2.1. Metal and Polymeric Repair Materials

Currently, joint repair systems often employ metal and/or polymericmaterials including, for example, prosthesis which are anchored into theunderlying bone (e.g., a femur in the case of a knee prosthesis). See,e.g., U.S. Pat. Nos. 6,203,576 and 6,322,588 and references citedtherein. A wide-variety of metals may find use in the practice of thepresent invention, and may be selected based on any criteria, forexample, based on resiliency to impart a desired degree of rigidity.Non-limiting examples of suitable metals include silver, gold, platinum,palladium, iridium, copper, tin, lead, antimony, bismuth, zinc,titanium, cobalt, stainless steel, nickel, iron alloys, cobalt alloys,such as Elgiloy®, a cobalt-chromium-nickel alloy, and MP35N, anickel-cobaltchromium-molybdenum alloy, and Nitinol™, a nickel-titaniumalloy, aluminum, manganese, iron, tantalum, other metals that can slowlyform polyvalent metal ions, for example to inhibit calcification ofimplanted substrates in contact with a patient's bodily fluids ortissues, and combinations thereof.

Suitable synthetic polymers include, without limitation, polyamides(e.g., nylon), polyesters, polystyrenes, polyacrylates, vinyl polymers(e.g., polyethylene, polytetrafluoroethylene, polypropylene andpolyvinyl chloride), polycarbonates, polyurethanes, poly dimethylsiloxanes, cellulose acetates, polymethyl methacrylates, polyether etherketones, ethylene vinyl acetates, polysulfones, nitrocelluloses, similarcopolymers and mixtures thereof. Bioresorbable synthetic polymers canalso be used such as dextran, hydroxyethyl starch, derivatives ofgelatin, polyvinylpyrrolidone, polyvinyl alcohol,poly[N-(2-hydroxypropyl)methacrylamide], poly(hydroxy acids),poly(epsilon-caprolactone), polylactic acid, polyglycolic acid,poly(dimethyl glycolic acid), poly(hydroxy butyrate), and similarcopolymers may also be used.

The polymers can be prepared by any of a variety of approaches includingconventional polymer processing methods. Preferred approaches include,for example, injection molding, which is suitable for the production ofpolymer components with significant structural features, and rapidprototyping approaches, such as reaction injection molding andstereo-lithography. The substrate can be textured or made porous byeither physical abrasion or chemical alteration to facilitateincorporation of the metal coating.

More than one metal and/or polymer may be used in combination with eachother. For example, one or more metal-containing substrates may becoated with polymers in one or more regions or, alternatively, one ormore polymer-containing substrate may be coated in one or more regionswith one or more metals.

The system or prosthesis can be porous or porous coated. The poroussurface components can be made of various materials including metals,ceramics, and polymers. These surface components can, in turn, besecured by various means to a multitude of structural cores formed ofvarious metals. Suitable porous coatings include, but are not limitedto, metal, ceramic, polymeric (e.g., biologically neutral elastomerssuch as silicone rubber, polyethylene terephthalate and/or combinationsthereof) or combinations thereof. See, e.g., Hahn U.S. Pat. No.3,605,123. Tronzo U.S. Pat. No. 3,808,606 and Tronzo U.S. Pat. No.3,843,975; Smith U.S. Pat. No. 3,314,420; Scharbach U.S. Pat. No.3,987,499; and German Offenlegungsschrift 2,306,552. There may be morethan one coating layer and the layers may have the same or differentporosities. See, e.g., U.S. Pat. No. 3,938,198.

The coating may be applied by surrounding a core with powdered polymerand heating until cured to form a coating with an internal network ofinterconnected pores. The tortuosity of the pores (e.g., a measure oflength to diameter of the paths through the pores) may be important inevaluating the probable success of such a coating in use on a prostheticdevice. See, also, Morris U.S. Pat. No. 4,213,816. The porous coatingmay be applied in the form of a powder and the article as a wholesubjected to an elevated temperature that bonds the powder to thesubstrate. Selection of suitable polymers and/or powder coatings may bedetermined in view of the teachings and references cited herein, forexample based on the melt index of each.

2.2. Biological Repair Materials

Repair materials may also include one or more biological material eitheralone or in combination with non-biological materials. For example, anybase material can be designed or shaped and suitable cartilagereplacement or regenerating material(s) such as fetal cartilage cellscan be applied to be the base. The cells can be then be grown inconjunction with the base until the thickness (and/or curvature) of thecartilage surrounding the cartilage defect has been reached. Conditionsfor growing cells (e.g., chondrocytes) on various substrates in culture,ex vivo and in vivo are described, for example, in U.S. Pat. Nos.5,478,739; 5,842,477; 6,283,980 and 6,365,405. Nonlimiting examples ofsuitable substrates include plastic, tissue scaffold, a bone replacementmaterial (e.g., a hydroxyapatite, a bioresorbable material), or anyother material suitable for growing a cartilage replacement orregenerating material on it.

Biological polymers can be naturally occurring or produced in vitro byfermentation and the like. Suitable biological polymers include, withoutlimitation, collagen, elastin, silk, keratin, gelatin, polyamino acids,cat gut sutures, polysaccharides (e.g., cellulose and starch) andmixtures thereof. Biological polymers may be bioresorbable.

Biological materials used in the methods described herein can beautografts (from the same subject); allografts (from another individualof the same species) and/or xenografts (from another species). See,also, International Patent Publications WO 02/22014 and WO 97/27885. Incertain embodiments autologous materials are preferred, as they maycarry a reduced risk of immunological complications to the host,including re-absorption of the materials, inflammation and/or scarringof the tissues surrounding the implant site.

In one embodiment of the invention, a probe is used to harvest tissuefrom a donor site and to prepare a recipient site. The donor site can belocated in a xenograft, an allograft or an autograft. The probe is usedto achieve a good anatomic match between the donor tissue sample and therecipient site. The probe is specifically designed to achieve a seamlessor near seamless match between the donor tissue sample and the recipientsite. The probe can, for example, be cylindrical. The distal end of theprobe is typically sharp in order to facilitate tissue penetration.Additionally, the distal end of the probe is typically hollow in orderto accept the tissue. The probe can have an edge at a defined distancefrom its distal end, e.g. at 1 cm distance from the distal end and theedge can be used to achieve a defined depth of tissue penetration forharvesting. The edge can be external or can be inside the hollow portionof the probe. For example, an orthopedic surgeon can take the probe andadvance it with physical pressure into the cartilage, the subchondralbone and the underlying marrow in the case of a joint such as a kneejoint. The surgeon can advance the probe until the external or internaledge reaches the cartilage surface. At that point, the edge will preventfurther tissue penetration thereby achieving a constant and reproducibletissue penetration. The distal end of the probe can include a blade orsaw-like structure or tissue cutting mechanism. For example, the distalend of the probe can include an iris-like mechanism consisting ofseveral small blades. The at least one or more blades can be moved usinga manual, motorized or electrical mechanism thereby cutting through thetissue and separating the tissue sample from the underlying tissue.Typically, this will be repeated in the donor and the recipient. In thecase of an iris-shaped blade mechanism, the individual blades can bemoved so as to close the iris thereby separating the tissue sample fromthe donor site.

In another embodiment of the invention, a laser device or aradiofrequency device can be integrated inside the distal end of theprobe. The laser device or the radiofrequency device can be used to cutthrough the tissue and to separate the tissue sample from the underlyingtissue.

In one embodiment of the invention, the same probe can be used in thedonor and in the recipient. In another embodiment, similarly shapedprobes of slightly different physical dimensions can be used. Forexample, the probe used in the recipient can be slightly smaller thanthat used in the donor thereby achieving a tight fit between the tissuesample or tissue transplant and the recipient site. The probe used inthe recipient can also be slightly shorter than that used in the donorthereby correcting for any tissue lost during the separation or cuttingof the tissue sample from the underlying tissue in the donor material.

Any biological repair material may be sterilized to inactivatebiological contaminants such as bacteria, viruses, yeasts, molds,mycoplasmas and parasites. Sterilization may be performed using anysuitable technique, for example radiation, such as gamma radiation.

Any of the biological material described herein may be harvested withuse of a robotic device. The robotic device can use information from anelectronic image for tissue harvesting.

In certain embodiments, the cartilage replacement material has aparticular biochemical composition. For instance, the biochemicalcomposition of the cartilage surrounding a defect can be assessed bytaking tissue samples and chemical analysis or by imaging techniques.For example, WO 02/22014 describes the use of gadolinium for imaging ofarticular cartilage to monitor glycosaminoglycan content within thecartilage. The cartilage replacement or regenerating material can thenbe made or cultured in a manner, to achieve a biochemical compositionsimilar to that of the cartilage surrounding the implantation site. Theculture conditions used to achieve the desired biochemical compositionscan include, for example, varying concentrations biochemical compositionof said cartilage replacement or regenerating material can, for example,be influenced by controlling concentrations and exposure times ofcertain nutrients and growth factors.

2.3. Multiple-Component Repair Materials

The articular surface repair system may include one or more components.Nonlimiting examples of one-component systems include a plastic, ametal, a metal alloy or a biologic material. In certain embodiments, thesurface of the repair system facing the underlying bone is smooth. Inother embodiments, the surface of the repair system facing theunderlying bone is porous or porous-coated.

Non-limiting examples of multiple-component systems include combinationsof metal, plastic, metal alloys and one or more biological materials.One or more components of the articular surface repair system can becomposed of a biologic material (e.g. a tissue scaffold with cells suchas cartilage cells or stem cells alone or seeded within a substrate suchas a bioresorable material or a tissue scaffold, allograft, autograft orcombinations thereof) and/or a non-biological material (e.g.,polyethylene or a chromium alloy such as chromium cobalt).

Thus, the repair system can include one or more areas of a singlematerial or a combination of materials, for example, the articularsurface repair system can have a superficial and a deep component. Thesuperficial component is typically designed to have size, thickness andcurvature similar to that of the cartilage tissue lost while the deepcomponent is typically designed to have a curvature similar to thesubchondral bone. In addition, the superficial component can havebiomechanical properties similar to articular cartilage, including butnot limited to similar elasticity and resistance to axial loading orshear forces. The superficial and the deep component can consist of twodifferent metals or metal alloys. One or more components of the system(e.g., the deep portion) can be composed of a biologic materialincluding, but not limited to bone, or a non-biologic materialincluding, but not limited to hydroxyapatite, tantalum, a chromiumalloy, chromium cobalt or other metal alloys.

One or more regions of the articular surface repair system (e.g., theouter margin of the superficial portion and/or the deep portion) can bebioresorbable, for example to allow the interface between the articularsurface repair system and the patient's normal cartilage, over time, tobe filled in with hyaline or fibrocartilage. Similarly, one or moreregions (e.g., the outer margin of the superficial portion of thearticular surface repair system and/or the deep portion) can be porous.The degree of porosity can change throughout the porous region, linearlyor non-linearly, for where the degree of porosity will typicallydecrease towards the center of the articular surface repair system. Thepores can be designed for in-growth of cartilage cells, cartilagematrix, and connective tissue thereby achieving a smooth interfacebetween the articular surface repair system and the surroundingcartilage.

The repair system (e.g., the deep component in multiple componentsystems) can be attached to the patient's bone with use of a cement-likematerial such as methylmethacrylate, injectable hydroxy- orcalcium-apatite materials and the like.

In certain embodiments, one or more portions of the articular surfacerepair system can be pliable or liquid or deformable at the time ofimplantation and can harden later. Hardening can occur within 1 secondto 2 hours (or any time period therebetween), preferably with in 1second to 30 minutes (or any time period therebetween), more preferablybetween 1 second and 10 minutes (or any time period therebetween).

One or more components of the articular surface repair system can beadapted to receive injections. For example, the external surface of thearticular surface repair system can have one or more openings therein.The openings can be sized so as to receive screws, tubing, needles orother devices which can be inserted and advanced to the desired depth,for example through the articular surface repair system into the marrowspace. Injectables such as methylmethacrylate and injectable hydroxy- orcalcium-apatite materials can then be introduced through the opening (ortubing inserted therethrough) into the marrow space thereby bonding thearticular surface repair system with the marrow space. Similarly, screwsor pins can be inserted into the openings and advanced to the underlyingsubchondral bone and the bone marrow or epiphysis to achieve fixation ofthe articular surface repair system to the bone. Portions or allcomponents of the screw or pin can be bioresorbable, for example, thedistal portion of a screw that protrudes into the marrow space can bebioresorbable. During the initial period after the surgery, the screwcan provide the primary fixation of the articular surface repair system.Subsequently, ingrowth of bone into a porous coated area along theundersurface of the articular cartilage repair system can take over asthe primary stabilizer of the articular surface repair system againstthe bone.

The articular surface repair system can be anchored to the patient'sbone with use of a pin or screw or other attachment mechanism. Theattachment mechanism can be bioresorbable. The screw or pin orattachment mechanism can be inserted and advanced towards the articularsurface repair system from a non-cartilage covered portion of the boneor from a non-weight-bearing surface of the joint.

The interface between the articular surface repair system and thesurrounding normal cartilage can be at an angle, for example oriented atan angle of 90 degrees relative to the underlying subchondral bone.Suitable angles can be determined in view of the teachings herein, andin certain cases, non-90 degree angles may have advantages with regardto load distribution along the interface between the articular surfacerepair system and the surrounding normal cartilage.

The interface between the articular surface repair system and thesurrounding normal cartilage may be covered with a pharmaceutical orbioactive agent, for example a material that stimulates the biologicalintegration of the repair system into the normal cartilage. The surfacearea of the interface can be irregular, for example, to increaseexposure of the interface to pharmaceutical or bioactive agents.

2.4. Customized Containers

In another embodiment of the invention, a container or well can beformed to the selected specifications, for example to match the materialneeded for a particular subject or to create a stock of repair materialsin a variety of sizes. The size and shape of the contained may bedesigned using the thickness and curvature information obtained from thejoint and from the cartilage defect. More specifically, the inside ofthe container can be shaped to follow any selected measurements, forexample as obtained from the cartilage defect(s) of a particularsubject. The container can be filled with a cartilage replacement orregenerating material, for example, collagen-containing materials,plastics, bioresorbable materials and/or any suitable tissue scaffold.The cartilage regenerating or replacement material can also consist of asuspension of stem cells or fetal or immature or mature cartilage cellsthat subsequently develop to more mature cartilage inside the container.Further, development and/or differentiation can be enhanced with use ofcertain tissue nutrients and growth factors.

The material is allowed to harden and/or grow inside the container untilthe material has the desired traits, for example, thickness, elasticity,hardness, biochemical composition, etc. Molds can be generated using anysuitable technique, for example computer devices and automation, e.g.computer assisted design (CAD) and, for example, computer assistedmodeling (CAM). Because the resulting material generally follows thecontour of the inside of the container it will better fit the defectitself and facilitate integration.

2.5. Shaping

In certain instances shaping of the repair material will be requiredbefore or after formation (e.g., growth to desired thickness), forexample where the thickness of the required cartilage material is notuniform (e.g., where different sections of the cartilage replacement orregenerating material require different thicknesses).

The replacement material can be shaped by any suitable techniqueincluding, but not limited to, mechanical abrasion, laser abrasion orablation, radiofrequency treatment, cryoablation, variations in exposuretime and concentration of nutrients, enzymes or growth factors and anyother means suitable for influencing or changing cartilage thickness.See, e.g., WO 00/15153; If enzymatic digestion is used, certain sectionsof the cartilage replacement or regenerating material can be exposed tohigher doses of the enzyme or can be exposed longer as a means ofachieving different thicknesses and curvatures of the cartilagereplacement or regenerating material in different sections of saidmaterial.

The material can be shaped manually and/or automatically, for exampleusing a device into which a pre-selected thickness and/or curvature hasbeen inputted and programming the device to achieve the desired shape.

In addition to, or instead of, shaping the cartilage repair material,the site of implantation (e.g., bone surface, any cartilage materialremaining, etc.) can also be shaped by any suitable technique in orderto enhanced integration of the repair material.

2.6. Pre-Existing Repair Systems

As described herein, repair systems of various sizes, curvatures andthicknesses can be obtained. These repair systems can be catalogued andstored to create a library of systems from which an appropriate systemcan then be selected. In other words, a defect is assessed in aparticular subject and a pre-existing repair system having the closestshape and size is selected from the library for further manipulation(e.g., shaping) and implantation.

2.7. Mini-Prosthesis

As noted above, the methods and compositions described herein can beused to replace only a portion of the articular surface, for example, anarea of diseased cartilage or lost cartilage on the articular surface.In these systems, the articular surface repair system may be designed toreplace only the area of diseased or lost cartilage or it can extendbeyond the area of diseased or lost cartilage, e.g., 3 or 5 mm intonormal adjacent cartilage. In certain embodiments, the prosthesisreplaces less than about 70% to 80% (or any value therebetween) of thearticular surface (e.g., any given articular surface such as a singlefemoral condyle, etc.), preferably, less than about 50% to 70% (or anyvalue therebetween), more preferably, less than about 30% to 50% (or anyvalue therebetween), more preferably less than about 20% to 30% (or anyvalue therebetween), even more preferably less than about 20% of thearticular surface.

As noted above, the prosthesis may include multiple components, forexample a component that is implanted into the bone (e.g., a metallicdevice) attached to a component that is shaped to cover the defect ofthe cartilage overlaying the bone. Additional components, for exampleintermediate plates, meniscus repairs systems and the like may also beincluded. It is contemplated that each component replaces less than allof the corresponding articular surface. However, each component need notreplace the same portion of the articular surface. In other words, theprosthesis may have a bone-implanted component that replaces less than30% of the bone and a cartilage component that replaces 60% of thecartilage. The prosthesis may include any combination, so long as eachcomponent replaces less than the entire articular surface.

The articular surface repair system may be formed or selected so that itwill achieve a near anatomic fit or match with the surrounding oradjacent cartilage. Typically, the articular surface repair system isformed and/or selected so that its outer margin located at the externalsurface will be aligned with the surrounding or adjacent cartilage.

Thus, the articular surface repair system can be designed to replaceonly the weight-bearing portion of an articular surface, for example ina femoral condyle. The weight-bearing surface refers to the contact areabetween two opposing articular surfaces during activities of normaldaily living. At least one or more weight-bearing portions can bereplaced in this manner, e.g., on a femoral condyle and on a tibia.

In other embodiments, an area of diseased cartilage or cartilage losscan be identified in a weight-bearing area and only a portion of saidweight-bearing area, specifically the portion containing said diseasedcartilage or area of cartilage loss, can be replaced with an articularsurface repair system.

In certain aspects, the defect to be repaired is located only on onearticular surface, typically the most diseased surface. For example, ina patient with severe cartilage loss in the medial femoral condyle butless severe disease in the tibia, the articular surface repair systemcan only be applied to the medial femoral condyle. Preferably, in anymethods described herein, the articular surface repair system isdesigned to achieve an exact or a near anatomic fit with the adjacentnormal cartilage.

In other embodiments, more than one articular surface can be repaired.

The area(s) of repair will be typically limited to areas of diseasedcartilage or cartilage loss or areas slightly greater than the area ofdiseased cartilage or cartilage loss within the weight-bearingsurface(s).

The implant and/or the implant site can be sculpted to achieve a nearanatomic alignment between the implant and the implant site. In anotherembodiment of the invention, an electronic image is used to measure thethickness, curvature, or shape of the articular cartilage or thesubchondral bone, and/or the size of a defect, and an articular surfacerepair system is selected using this information. The articular surfacerepair system can be inserted arthroscopically. The articular surfacerepair system can have a single radius. More typically, however, thearticular surface repair system 1100 can have varying curvatures andradii within the same plane, e.g. anteroposterior or mediolateral orsuperoinferior or oblique planes, or within multiple planes. In thismanner, the articular surface repair system can be shaped to achieve anear anatomic alignment between the implant and the implant site. Thisdesign allows not even for different degrees of convexity or concavity,but also for concave portions within a predominantly convex shape orvice versa 1100.

If a multiple component repair material has been selected, for examplewith a superficial component 1105 consisting of a polymeric material anda deep component 1110 consisting of a metal alloy, the superficialcomponent can be designed so that its thickness and curvature willclosely match that of the surrounding cartilage 1115. Thus, thesuperficial component can have more than one thickness in differentportions of the articular repair system. Moreover, the superficialcomponent can have varying curvatures and radii within the same plane,e.g. anteroposterior or mediolateral or superoinferior or obliqueplanes, or within multiple planes. Similarly, the deep component canhave varying curvatures and radii within the same plane, e.g.anteroposterior or mediolateral or superoinferior or oblique planes, orwithin multiple planes. Typically, the curvature of the deep componentwill be designed to follow that of the subchondral bone.

In another embodiment the articular surface repair system has afixturing stem, for example, as described in the Background of U.S. Pat.No. 6,224,632. The fixturing stem can have different shapes includingconical, rectangular, fin among others. The mating bone cavity istypically similarly shaped as the corresponding stem.

In another embodiment, the articular surface repair system can beattached to the underlying bone or bone marrow using bone cement. Bonecement is typically made from an acrylic polymeric material. Typically,the bone cement is comprised of two components: a dry power componentand a liquid component, which are subsequently mixed together. The drycomponent generally includes an acrylic polymer, such aspolymethylmethacrylate (PMMA). The dry component can also contain apolymerization initiator such as benzoylperoxide, which initiates thefree-radical polymerization process that occurs when the bone cement isformed. The liquid component, on the other hand, generally contains aliquid monomer such as methyl methacrylate (MMA). The liquid componentcan also contain an accelerator such as an amine (e.g.,N,N-dimethyl-p-toluidine). A stabilizer, such as hydroquinone, can alsobe added to the liquid component to prevent premature polymerization ofthe liquid monomer. When the liquid component is mixed with the drycomponent, the dry component begins to dissolve or swell in the liquidmonomer. The amine accelerator reacts with the initiator to form freeradicals that begin to link monomer units to form polymer chains. In thenext two to four minutes, the polymerization process proceeds changingthe viscosity of the mixture from a syrup-like consistency (lowviscosity) into a dough-like consistency (high viscosity). Ultimately,further polymerization and curing occur, causing the cement to hardenand affix a prosthesis to a bone.

In certain aspects of the invention, bone cement 955 or another liquidattachment material such as injectable calciumhydroxyapatite can beinjected into the marrow cavity through one or more openings 950 in theprosthesis. These openings in the prosthesis can extend from thearticular surface to the undersurface of the prosthesis 960. Afterinjection, the openings can be closed with a polymer, silicon, metal,metal alloy or bioresorbable plug.

In another embodiment, one or more components of the articular surfacerepair (e.g., the surface of the system that is pointing towards theunderlying bone or bone marrow) can be porous or porous coated. Avariety of different porous metal coatings have been proposed forenhancing fixation of a metallic prosthesis by bone tissue ingrowth.Thus, for example, U.S. Pat. No. 3,855,638 discloses a surgicalprosthetic device, which may be used as a bone prosthesis, comprising acomposite structure consisting of a solid metallic material substrateand a porous coating of the same solid metallic material adhered to andextending over at least a portion of the surface of the substrate. Theporous coating consists of a plurality of small discrete particles ofmetallic material bonded together at their points of contact with eachother to define a plurality of connected interstitial pores in thecoating. The size and spacing of the particles, which can be distributedin a plurality of monolayers, can be such that the average interstitialpore size is not more than about 200 microns. Additionally, the poresize distribution can be substantially uniform from thesubstrate-coating interface to the surface of the coating.

In another embodiment, the articular surface repair system can containone or more polymeric materials that can be loaded with and releasetherapeutic agents including drugs or other pharmacological treatmentsthat can be used for drug delivery. The polymeric materials can, forexample, be placed inside areas of porous coating. The polymericmaterials can be used to release therapeutic drugs, e.g. bone orcartilage growth stimulating drugs. This embodiment can be combined withother embodiments, wherein portions of the articular surface repairsystem can be bioresorbable. For example, the superficial layer of anarticular surface repair system or portions of its superficial layer canbe bioresorbable. As the superficial layer gets increasingly resorbed,local release of a cartilage growth-stimulating drug can facilitateingrowth of cartilage cells and matrix formation.

In any of the methods or compositions described herein, the articularsurface repair system can be pre-manufactured with a range of sizes,curvatures and thicknesses. Alternatively, the articular surface repairsystem can be custom-made for an individual patient.

3. Implantation

Following one or more manipulations (e.g., shaping, growth, development,etc), the cartilage replacement or regenerating material can then beimplanted into the area of the defect. Implantation can be performedwith the cartilage replacement or regenerating material still attachedto the base material or removed from the base material. Any suitablemethods and devices may be used for implantation, for example, devicesas described in U.S. Pat. Nos. 6,375,658; 6,358,253; 6,328,765; andInternational Publication WO 01/19254.

In selected cartilage defects, the implantation site can be preparedwith a single cut across the articular surface (FIG. 10). In this case,single 1010 and multi-component 1020 prostheses can be utilized.

Further, implantation can be facilitated by using a device applied tothe outer surface of the articular cartilage in order to match thealignment of the donor tissue and the recipient site. The device can beround, circular, oval, ellipsoid, curved or irregular in shape. Theshape is typically selected or adjusted to match or enclose an area ofdiseased cartilage or an area slightly larger than the area of diseasedcartilage. The inner aspect of the circle, oval, ellipse, curved orirregular shape can be open or hollow. Thus, a rounded or curved jointsurface such as a femoral condyle, a femoral head or a humeral head canprotrude through the opening or the hollow portion. The device caninclude a slit through which a blade can be introduced. Alternatively,the device can include a blade holding mechanism or the blade can beintegrated in the device. A variety of materials can be employed, forexample plastic (e.g., disposable, re-usable and/or sterilizable)devices. In addition, translucent materials may be used, for example inorder to achieve an improved match between the donor tissue and therecipient site.

The device can be used to remove an area of diseased cartilage andunderlying bone or an area slightly larger than the diseased cartilageand underlying bone. In addition, the device can be used on a “donor”,e.g. a cadaveric specimen to obtain implantable repair material. Thedevice is typically positioned in the same general anatomic area inwhich the tissue was removed in the recipient. The shape of the deviceis then used to identify a donor site providing a seamless or nearseamless match between the donor tissue sample and the recipient site.This is achieved by identifying the position of the device in which thearticular surface in the donor, e.g. a cadaveric specimen has a seamlessor near seamless contact with the inner surface when applied to thecartilage.

The device can be molded, machined or formed based on the size of thearea of diseased cartilage and based on the curvature of the cartilageor the underlying subchondral bone or a combination of both. The devicecan then be applied to the donor, (e.g., a cadaveric specimen) and thedonor tissue can be obtained with use of a blade or saw or other tissuecutting device. The device can then be applied to the recipient in thearea of the diseased cartilage and the diseased cartilage and underlyingbone can be removed with use of a blade or saw or other tissue cuttingdevice whereby the size and shape of the removed tissue containing thediseased cartilage will closely resemble the size and shape of the donortissue. The donor tissue can then be attached to the recipient site. Forexample, said attachment can be achieved with use of screws or pins(e.g., metallic, non-metallic or bioresorable) or other fixation meansincluding but not limited to a tissue adhesive. Attachment can bethrough the cartilage surface or alternatively, through the marrowspace.

The implant site can be prepared with use of a robotic device. Therobotic device can use information from an electronic image forpreparing the recipient site.

What is claimed is:
 1. A method for making an implant for repairing ajoint of a patient, comprising: obtaining electronic image data fromthree dimensional or two dimensional images of one or more portions ofthe joint of the patient; providing a cut along a surface of the jointderived from the electronic image data, wherein the cut surfacecomprises an outer periphery; and designing or selecting an implantcomprising an outer periphery that substantially matches the outerperiphery of the cut surface
 2. The method of claim 1, wherein the jointof the patient is a knee joint of the patient, wherein the surface ofthe joint includes a tibial plateau of the knee joint of the patientderived from the electronic image data.